{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Bubenik M"],"funding":["Ono Pharmaceutical","NCI NIH HHS","Canadian Institutes of Health Research","NIGMS NIH HHS","NIH HHS"],"pagination":["13198-13215"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9942948"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["65(19)"],"pubmed_abstract":["DNA polymerase theta (Polθ) is an attractive synthetic lethal target for drug discovery, predicted to be efficacious against breast and ovarian cancers harboring BRCA-mutant alleles. Here, we describe our hit-to-lead efforts in search of a selective inhibitor of human Polθ (encoded by POLQ). A high-throughput screening campaign of 350,000 compounds identified an 11 micromolar hit, giving rise to the N2-substituted fused pyrazolo series, which was validated by biophysical methods. Structure-based drug design efforts along with optimization of cellular potency and ADME ultimately led to the identification of <b>RP-6685</b>: a potent, selective, and orally bioavailable Polθ inhibitor that showed in vivo efficacy in an HCT116 BRCA2<sup>-/-</sup> mouse tumor xenograft model."],"journal":["Journal of medicinal chemistry"],"pubmed_title":["Identification of <b>RP-6685</b>, an Orally Bioavailable Compound that Inhibits the DNA Polymerase Activity of Polθ."],"pmcid":["PMC9942948"],"funding_grant_id":["PJT-178026","P30 CA008748","P30 GM124165","FDN-143277","S10 OD021527","PJT-180338"],"pubmed_authors":["Martino G","Casas-Selves M","Ciblat S","Clark J","Chefson A","Poirier H","Roulston A","Morris SJ","Mochirian P","Leclaire ME","Parikh P","Papp R","Bubenik M","Baruah PS","Patel P","Gervais C","Stocco R","Pinter T","Sicheri F","Dorich S","Gallant M","Duffy NM","El Bakkouri M","Vallee F","Falgueyret JP","Barabe F","Nicolas O","Mathieu MC","St-Onge M","Sfeir A","Truchon JF","Pellerin C","Pau V","Zahn KE","Godbout C","Black WC","Kurinov I","Perryman AL","Mamane Y","Fortin AB","Mader P","Hamel M"],"additional_accession":[]},"is_claimable":false,"name":"Identification of <b>RP-6685</b>, an Orally Bioavailable Compound that Inhibits the DNA Polymerase Activity of Polθ.","description":"DNA polymerase theta (Polθ) is an attractive synthetic lethal target for drug discovery, predicted to be efficacious against breast and ovarian cancers harboring BRCA-mutant alleles. Here, we describe our hit-to-lead efforts in search of a selective inhibitor of human Polθ (encoded by POLQ). A high-throughput screening campaign of 350,000 compounds identified an 11 micromolar hit, giving rise to the N2-substituted fused pyrazolo series, which was validated by biophysical methods. Structure-based drug design efforts along with optimization of cellular potency and ADME ultimately led to the identification of <b>RP-6685</b>: a potent, selective, and orally bioavailable Polθ inhibitor that showed in vivo efficacy in an HCT116 BRCA2<sup>-/-</sup> mouse tumor xenograft model.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Oct","modification":"2026-05-28T16:21:58.924Z","creation":"2024-12-03T21:31:50.385Z"},"accession":"S-EPMC9942948","cross_references":{"pubmed":["36126059"],"doi":["10.1021/acs.jmedchem.2c00998"]}}